Lee, Min Sun Jung, Byung Hwa Chung, Bong Chul Cho, Sung Hee Kim, Ki Young Kwon, Oh Seoung Nugraha, Boya Lee, Young-Joo 2024-01-20T20:35:21Z 2024-01-20T20:35:21Z 2021-09-05 2009-09 1091-5818 https://pubs.kist.re.kr/handle/201004/132191 Three different doses of valproic acid (20, 100, and 500 mg/kg/d) are administered orally to Sprague-Dawley rats for 5 days, and the feasibility of metabolomics with gas chromatography-mass spectrometry as a predictor of the hepatotoxicity of valproic acid is evaluated. Body weight is found to decrease with the 100-mg/kg/d dose and significantly decrease with the 500-mg/kg/d dose. Mean excreted urine volume is lowest in the 500-mg/kg/d group among all groups. The plasma level of alpha-glutathione-S-transferase, a sensitive and earlier biomarker for hepatotoxicity, increases significantly with administration of 100 and 500 mg/kg/d; however, there is not a significant difference in alpha-glutathione-S-transferase plasma levels between the control and 20-mg/kg/d groups. Clusters in partial least squares discriminant analysis score plots show similar patterns, with changes in physiological conditions and plasma levels of alpha-glutathione-S-transferase; the cluster for the control and 20-mg/kg/d groups does not clearly separate, but the clusters are separate for 100- and 500-mg/kg/d groups. A biomarker of hepatotoxicity, 8-hydroxy-2'-deoxyguanosine and octanoylcarnitine, is identified from nontargeted and targeted metabolic profiling. These results validate that metabolic profiling using gas chromatography-mass spectrometry could be a useful tool for finding novel biomarkers. Thus, a nontargeted metabolic profiling method is established to evaluate the hepatotoxicity of valproic acid and demonstrates proof-of-concept that metabolomic approach with gas chromatography-mass spectrometry has great potential for predicting valproic acid-induced hepatotoxicity and discovering novel biomarkers. English SAGE PUBLICATIONS INC Metabolomics Study With Gas Chromatography-Mass Spectrometry for Predicting Valproic Acid-induced Hepatotoxicity and Discovery of Novel Biomarkers in Rat Urine Article 10.1177/1091581809340329 1 INTERNATIONAL JOURNAL OF TOXICOLOGY, v.28, no.5, pp.392 - 404 INTERNATIONAL JOURNAL OF TOXICOLOGY 28 5 392 404 N scie scopus 000270635800006 2-s2.0-73149108642 Pharmacology & Pharmacy Toxicology Pharmacology & Pharmacy Toxicology Article GLUTATHIONE-S-TRANSFERASE SWITCHING LIQUID-CHROMATOGRAPHY QUANTITATIVE-DETERMINATION HEPATOCELLULAR-DAMAGE LIPID-PEROXIDATION OXIDATIVE DAMAGE CARNITINE PLASMA LIVER DNA valproic acid hepatotoxicity metabolic profiling metabolomics gas chromatography-mass spectrometry